We propose a Specialized Center of Research in Sudden Death at the University of Utah to investigate the relationship between abnormalities of repolarization and arrhythmic death. The investigative group is composed of 17 investigators and 8 consultants. Four Research Projects and four Core support laboratories are proposed. The first research project, lonic Mechanisms of Repolarization in Human Ventricular Myocytes, directed by MC Sanguinetti, centers on K+ and other repolarizing currents. Voltage clamp techniques are applied to isolated human myocytes to determine which currents are present, to fully characterize them and to determine how they influence normal and abnormal repolarization processes. In Project 2, Molecular and Physiologic Mechanisms of the Long QT Syndrome, MT Keating and colleagues investigate the molecular genetics and the cardiac electrophysiology of this inherited form of arrhythmia in man and in human myocardium. JW Mason and coworkers plan studies of repolarization changes that occur immediately preceding sudden death due to ischemia in the third project, Repolarization Changes Associated with Ventricular Arrhythmias and Sudden Death. In Project 4, Electrocardiographic Measures of Ventricular Repolarization, techniques for non-invasive measurement of regional cardiac repolarization and disparity of repolarization are developed by LS Green, RL Lux and colleagues for diagnosis and prognostication in man. The Administrative Core, led by Mason, will provide assistance to all investigators in budget management and intercommunication. Core 2, the Cell Processing Laboratory directed by WH Barry and GA Peeters, will prepare isolated human ventricular myocytes for Projects 1 and 2, maintain and culture frog oocytes for Project 1, and transform and maintain peripheral blood lymphocytes from patients with LQT for DNA analysis in Project 2. Core 3, the Repolarization Signal Processing Laboratory led by Lux, will provide electrocardiographic signal processing and interpretation capabilities to Projects 2, 3 and 4. TE Moon directs the fourth Core laboratory, Clinical Data Management and Biostatistics, which will assist Project 2, 3 and 4 investigators in collection, statistical analysis and interpretation of clinical data obtained from patients. This SCOR proposal is sharply focussed on a single facet of the problem of sudden death. It combines basic science with whole-organ physiology and complex clinical medicine. It is likely to produce insight into the pathophysiology of sudden death and lead to improvements in therapy while establishing a framework for future fundamental discoveries.